1. family and parenting
2. motherhood
3. pregnancy

Changes in Pharmacokinetics
and Pharmacodynamics During
Pregnancy
CARLA JANZEN, MD, PhD
2013
Department of Obstetrics and Gynecology
Division of Maternal-Fetal Medicine
Pharmacokinetics
“What the body does to the
drug”
• Absorption
– Bioavailability
• Extent drug dose reaches
the circulation unchanged
• Distribution
• Plasma protein binding
• Metabolism
• Termination of activity
• Elimination
Pharmacodynamics
“What the drug does to the body”
•
To produce its specific biologic effects,
a drug must be in appropriate
concentrations at its sites of action
•
In Phase I: healthy volunteers
– evaluate its safety
– determine a safe dosage range
– identify adverse effects doses
(toxicology).
Phase II:
– Effective (=pharmacology).
Phase III:
– Compare to commonly used
treatments
•
•
History of Women in Clinical Trials
• Before 1993, the FDA excluded women
from most clinical studies.
– FDA guidelines
• no women of child-bearing potential in
Phase I and Phase II trials.
• Child bearing potential
– any woman physiologically capable of
becoming pregnant
• regardless of sexual activity/ practices and
contraceptive use
• Argument for excluding women
– Safety of the fetus if pregnancy were to occur
during the trial.
– Pregnant women, fetuses and neonates are
a vulnerable population.
Thalidomide
• 1956: a sedative prescribed in
Germany for nausea and insomnia.
• 1960 Grunenthal applied to FDA for
approval to sell thalidomide in U.S
(rodents in pre-market studies).
• Frances Kelsey MD, PhD
– first drug review case for FDA
• rejected application 6 times
• Interested in fetal safety- Had studied quinine in
1940s
– Perhaps thalidomide could cross placenta?
(rabbit study)
– No data had been provided on human
metabolism, PK
Thalidomide
• 1961: discovered that drug
– Causes miscarriage
– Stunts growth of fetal limbs
• 20,000 children affected
• 1962 FDA
– Commission on Drug Safety
founded
Patient Perception
• Pregnant women believe almost any drug is
teratogenic.
– Unnecessary anxiety
• Survey: women exposed to acetaminophen and dental x-rays
considered themselves to be at 24% risk (similar to
thalidomide).
• Goal: focus on prevention of malformation in
cases where women are exposed to known
teratogens.
– Evidence based counseling.
Obstetric Pharmacology
• Off-label drug use common
– 50% pregnant women take at least one
medication
• 92% Prenatal Vitamins
• 35% antibiotics
• 8% opioids
• Most drugs used in pregnancy have no data on dosage
and safety.
• NOT having accurate drug efficacy and safety data in
pregnancy = higher risk than that associated with
– women in clinical trials becoming pregnant and exposing the
fetus to the trial drug.
Obstetric Pharmacology
• 1990, the NIH directed that women and minorities be
included in clinical trials.
– “…the study of drugs used in pregnancy is one of the most
neglected areas in the field of clinical pharmacology and drug
research.”
• 1994 FDA created Office of Women’s Health (OWH)
– Pendulum: moderate protectionism
• Info on HOW to include vulnerable populations
• Informed consent
• 2004 Obstetric-Fetal Pharmacology Research Unit
(OPRU)
– 4 Sites: UTMB, Magee, U Washington, Georgetown
– Focus: to expand knowledge of pharmacology during pregnancy
• Clearance for almost all drugs increases in pregnancy.
SEX DIFFERENCES
• Physiological factors
• Molecular factors
SEX DIFFERENCES
• 2001: review of 10 drugs
withdrawn from U.S. market
(1997-2000).
• 9/10 were associated with
greater ADRs in women over
men.
– QT prolongation
– Hepatic toxicity
• 2000 cases of liver failure/yr
– ¾ are women.
• If these drugs had been
evaluated in both men and
women, there would have
been an indication that sex
differences exist.
SEX DIFFERENCES
• Physiological factors
– The length of QT interval is androgen dependent, with
QT intervals longer in women than men.
• The longer the QT interval, the greater the likelihood of
arrhythmia.
– Generally lower
• Body weight
• Organ size
• Glomerular filtration rate
– Generally higher
• Percentage of body fat (affects Vd: smaller for ethanol).
Pharmacokinetics
“What the body does to the drug”
DistributionRate at which equilibrium between tissue
and plasma concentration is achieved
depends on:
•
Drug’s ability to bind to proteins or
tissues
• Drug lipid solubility
– Water soluble
• will cross cell membranes only if
small molecular size
– Lipid soluble
• more likely to cross biological
barriers
– cell membranes
– blood-brain barrier
– placenta
Pharmacokinetics
“What the body does to the drug”
MetabolismMajor determinant of drug clearance
• Drug solubility
– Water soluble
• Eliminated unchanged after glomerular filtration
– Lipid-soluble
• Series of Reactions to render drug more polar for excretion in bile or urine
• Phase I; CYP
– responsible for inter-individual differences in drug pharmacokinetics.
– Ethnicity
– Gender
– Pregnancy
• Phase II
Metabolism
• Phase I
– Generate metabolites that are polar than the
parent compound. Functional group added that
can undergo phase II reaction.
– Phase I reaction can lead to the formation of
• Inactive metabolite
• Prodrug  active form of drug
H
• Toxic metabolites.
O
H
H
O
N
N
O
PHENYTOIN
H
OH
N
N
O
p - HPPH
Metabolism
• Phase II
– Conjugation of parent molecule or phase I
metabolite.
• Glutathione
• Conjugates are more water-soluble and
less active (less toxic) than nonconjugated
compounds.
Metabolism: Cytochrome P450
• Heme Protein
– Major player in oxidative
metabolism.
• Encoded by gene
superfamily-hundred of
genes.
• Substrates include
– Endobiotics- steroid
hormones
– Xenobiotics- inactivation
of drugs
Metabolism: Cytochrome P450
GI, lungs, kidneys
-Extrahepatic microsomal enzymes
(oxidation, conjugation)
Liver
-Hepatic microsomal enzymes
(oxidation, conjugation)
Hepatic non-microsomal enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)
Cytochrome P450
• Men seem to have higher activity relative
to women for:
– Cyp 1A
– Cyp 2D
– Cyp 2E
• Women have higher
– Cyp 3A4 activity
• Pregnancy increases further
Cytochrome P450
•
Genetic Polymorphisms result in differences in gene expression.
•
CYP 2D6 Fast metabolizers
–
–
activity increased (codeine metabolized to morphine)
Increased toxicity
Case Study (Lancet 2006): Healthy full term newborn died at 13 days from morphine poisoning.
–
–
–
–
Mother with genetic polymorphism CYP2D6 (increased activity during pregnancy)
Codeine was prescribed for episiotomy pain
Breastfeeding
Ultrarapid metabolizer
•
–
•
Baby with extremely high blood morphine concentration
CYP 2D6 Poor metabolizers
–
–
Activity decreased → No drug effect
Example= Fluoxetine (metabolized to an active compound)
•
•
codeine to morphine
increased dose of antidepressants needed to maintain efficacy in poor metabolizers
Inducible expression (activity and level) by nongenetic factors
–
–
Dietary habits (grapefruit juice ↓ intestinal CYP3A4  increased calcium channel blocker concentration
Smoking (induces CYP1A2)
Pregnancy
Cardiovascular
Respiratory
Renal
GI
Endocrine
Blood
Skin
Weight Gain
• 2/3 of weight gain is total body water
– 40% -- fetal compartment
– 60% -- maternal compartment
Blood Volumes
(% control)
• Total body water increases - up to 8 liters
• Plasma volume increases by 50%
• Maternal cardiac output increases by 30-50% during
pregnancy (4.5 l/min  6 l/min)
– Enhances GFR/renal excretion of drugs
– Example: atenolol clearance increases by 36%.
PK and Physiological Changes In Pregnancy
• Ingestion
• Compliance
– Fear that fetus may be harmed
– Nausea, vomiting and heartburn
• Absorption
• Gastric
– Delayed gastric emptying
– Gastric acid secretion is decreased by 40%
Epidural space
– Greatly increased vascularity in epidural space
– Demerol more rapidly absorbed
• Distribution
– Decreased albumin concentration (hemodilution)
• Metabolism
– Unpredictable ( CYP2D6, CYP3A4, CYP1A2)
• Elimination
– 40% Increased renal blood flow,
» Increased clearance of water-soluble drugs
» Ex: ampicillin, lithium
Drug Effects of Pregnancy
•
Caffeine increased concentration.
– Water soluble
• Vd increases, and concentration falls due to increased total body water
– Metabolized by CYP1A2
• Decreased during pregnancy
Weeks
•
•
•
•
Clearance
Half-Life
11
17
24
32
100%
68%
54%
37%
5.3h
9.9h
12.6h
10h
• PP
100%
5.5h
– Pregnant women spontaneously reduce amt of caffeinated beverages they drink.
Principles of Teratology
•
Teratogenic agent- potential to interfere with the normal functional/structural
development of an embryo or fetus.
– generally thought of as major congenital anomalies
– also may increase risk for a spectrum of adverse pregnancy outcomes (abortion,
minor structural anomalies, shortened gestational age, growth restriction, and
behavioral or cognitive deficits)
•
•
•
•
•
•
•
•
•
•
Anticonvulsants
Antineoplastic agents
inhibitors of angiotensinogen-angiotensin pathway
Methylmercury
Cocaine
Alcohol
Hyperthermia
Tetracycline
Warfarin
Isotretinoin
Principles of Teratology
1970s Wilson and Fraser, basic principles of teratology
• species specificity
–
•
genetic susceptibility
–
•
Isotretinoin (Accutane) taken orally→ potent human teratogen
topical retinoids →have not been associated with increased risk for adverse effects
spectrum of outcomes (eg, alcohol)
–
•
Higher doses cause higher frequency of defect
route of administration
–
–
•
Exposure during the formation of organ. eg, Carbamazepine (Tegretol), anticonvulsant
linked to a 10-fold increased risk for neural tube defects (28 days after conception…no effect
after 1st trimester).
dose response
–
•
Polymorphisms
gestational timing
–
•
thalidomide was not teratogenic in rodents
depending on dose and timing in gestation, effects range from spontaneous abortion to major
structural defects, prenatal or postnatal growth deficiency, preterm delivery and deficits in IQ
specific mechanisms leading to pathogenesis
–
act on specific targets to produce a characteristic pattern of effects
•
increase the risk for neural tube defects via folate antagonism
Data on Exposures in Pregnancy
•
For most exposures, reliable information is limited.
•
Human safety data for US prescription medications over 20 years (Lo and
Friedman)
– There is insufficient data to rule out teratogenicity for more than 80% of drugs
•
Clinical trials for prescription medications are not typically conducted in
human pregnancy
– pharmaceutical industry has no incentive to do so.
•
Animal reproductive and developmental toxicity studies are used to estimate
the potential for human teratogenicity.
– however, animal studies are not completely predictive of human pregnancy
outcomes
• species sensitivity
• differences in dosing and exposure timing
Adverse Case Reports
• When new medications are marketed in the
United States
– initial reports of pregnancy exposures with adverse
outcomes:
• safety data provided to the FDA by manufacturers
• case reports in the literature
• voluntary reports by clinicians or patients.
• Weaknesses:
– data sources lack information about the number of
exposed pregnancies with normal outcomes
• confuse the process of determining whether the adverse
event reports represent an excess risk over the baseline for
that event.
Pregnancy Registries
•
Prospective collection of data re: exposures to a specific drug
–
•
Outcome of interest: major birth defects
Strengths
– potential for gathering early information about a new drug
•
Weaknesses:
– lack formal comparison groups (compared to background population)
– typically have outcome data on small numbers of pregnancies.
– Small sample sizes  Only pick up dramatically increased birth defect rate
•
Collaborative registry designs such as the Antiepileptic Drugs in
Pregnancy Registry have demonstrated success in identifying signals or
establishing higher than expected rates for major birth defects after selected
exposures
Observational Cohort Studies
• Prospectively designed exposure cohort studies in which women
with and without the exposure of interest are enrolled during
pregnancy and followed to outcome.
• Strengths:
– Goal of testing a specific hypothesis
– ability to evaluate a spectrum of outcomes, including major and minor
malformations
– include a comparison group or groups, allowing for the control of key
factors that may be confounders
• maternal age socioeconomic status, and alcohol or tobacco use.
• Such a study design was successful identifying carbamazepine as a
human teratogen.
• Weakness:
– Small sample sizes 
rate
Only pick up dramatically increased birth defect
Database Cohorts
• Historical cohort using archived information in existing databases.
– For example, HMO claims data and records from government-supported
healthcare agencies analyzed for information on pregnancies with or
without specific medication exposures.
• Strengths:
– cost savings for collecting data for a given number of pregnancies
• Weaknesses:
– Database studies rely on information not collected primarily for research
purposes
• validation of exposure and outcome, as well as data on some key potential
confounders, may be difficult or impossible to obtain.
• Database cohorts have been used to identify a possible link
between paroxetine and congenital heart defects.
Case-Control Studies
•
Pregnancies are retrospectively selected
–
–
•
specific outcome, such as a particular birth defect.
The frequency of exposure to an agent of interest among mothers of affected infants is
compared with the frequency among mothers whose pregnancies did not result in that birth
defect.
Strengths:
–
With proper numbers of cases and controls,
•
–
provide sufficient power to detect increased risks for rare outcomes.
Control group: collects information on potential confounding variables
•
age, socioeconomic status, alcohol and tobacco use
•
The case-control approach was used successfully to identify the association of
misoprostol (used to induce abortion) with a very high risk for a rare congenital facial
nerve paralysis, Möbius syndrome.
•
Weaknesses:
–
–
Lag time inherent in collecting information on a new drug, especially if it is infrequently used
by pregnant women
possible that women who are already aware of a negative outcome of their pregnancy may
recall exposures more carefully (or incorrectly) than those who had a normal outcome.
Summary
•
Drug disposition and response differs not only between men and women but
also between pregnant and nonpregnant women.
– More research is needed to understand how pregnancy alters the PK and PD of
drugs
•
Randomized trials to demonstrate efficacy
• easier to demonstrate than safety
– Birth defects
• Background risk is 2-3% of population
• To find specific birth defect that occurs at a rate of 1 in 1,000 or fewer,
– to demonstrate drug does not produce a specific birth defect requires >100,000 pregnant
women
•
Evidence based counseling.
– Preconception counseling ideal: understand and weigh the risks of
complications of medical condition versus side effects of medications.
ACE inhibitors
Calvarial hypoplasia, renal dysgenesis,
oligohydramnios, IUGR, and neonatal renal
failure
second and third trimester
Alcohol
growth restriction, microcephaly, craniofacial
dysmorphology (1–4/1000 live births); renal,
cardiac, and other major malformations
late pregnancy use is associated with IUGR and
developmental delay; incidence is 4–44%
among “heavy drinkers”
chronic daily ingestion of at least 2 grams
alcohol/kg (8 drinks per day).
Antidepressants (SSRIs)
Possible cardiac defects, NTDs, omphalocele;
neonata pulmonary hypertension and
withdrawal syndrome
Aminopterin, methotrexate
calvarial hypoplasia, craniofacial abnormalities,
limb defects; possible developmental delay
Carbamazepine
NTDs (1%)
possible facial hypoplasia and developmental
delay
Corticosteroids
Cleft lip/palate increased threefold to sixfold;
IUGR increased with high doses
Lithium
Ebstein cardiac anomaly
Phenytoin
IUGR, microcephaly, facial hypoplasia,
hypertelorism, prominent upper lip (10%);
possible developmental delay
Streptomycin
Hearing loss, eighth nerve damage
Tetracycline
Discoloration of deciduous teeth and enamel
hypoplasia
Tobacco
Oral clefts: relative risk, 1.22–1.34; IUGR, IUFD,
abruption
Valproic acid
NTDs (1–2%); facial hypoplasia, possible
developmental delay
Warfarin
nasal hypoplasia, stippled epiphyses, growth
restriction (6%); also increased microcephaly,
Dandy-Walker syndrome, IUGR, preterm birth,
mental retardation
Syndrome associated with methotrexate >10
mg/wk
Greatest risk is at 6–9 wk
Resource
• http://www.otispregnancy.org/hm/
– 866-626-6847
• www.reprotox.org
• www.FDA.gov
• www.CDC.gov